Download Primary Immunodeficiencies

CLASS: HOUR 2
DATE 11-17-10
PROFESSOR: Atkinson
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Primary Immunodeficiencies
Scribe: Spencer Terry
Proof: Ashley Tate
Page 1 of 5
Primary Immunodeficiencies [S1]
a. Talking about Immunodeficiencies. Individually, they are pretty rare disorders. Although, some of the milder
ones are fairly common.
b. They are diseases that in aggregate, you will probably run across in some patients, and sometimes there are
clues. Healthcare providers worry about these patients.
c. Sometimes there are clues that help with diagnosis. We have had patients referred to us, particularly by
dentists, who turned out to have inflammatory problems, Immunodeficiencies, and autoimmunity.
d. Don’t fixate too much on individual diseases. There are 3 to 4 prototypical diseases, but don’t worry about
laundry lists. More interested in the presentation that the patients have. (A long history of infection, what type
of disease would you think about?)
Overview of the Primary Immunodeficiencies [S2]
a. These diseases are compartmentalized into several different areas.
b. There can be inherited diseases that purely affect the T cell function. These may be relatively mild or
extremely severe. You can’t really make any antibodies at all if your T cell function is impaired. These
patients also have a secondary B cell dysfunction as well.
c. There are also disorders where it is a purely antibody problem. There is a disorder that is preventing them
from making adequate antibodies, but their T cells work fine.
d. SCID is a syndrome in early infancy in which there is severe dysfunction in the immune system, usually
caused by either a selective severe defect in T cell or T cell and B cell dysfunction.
e. Any time you have a T cell problem, you are going to have a B cell problem as well.
f. The combined Immunodeficiencies are patients with T and B cell deficiencies are those that are not so severe
to call for bone marrow transplant in infancy, but are more of a long term problem related to recurrent
infections. These can be more of a problem to deal with that the SCID’s because SCID’s always go to bone
marrow transplant in early infancy, so they are left with fairly normal immune function afterwards.
g. There are a variety of disorders of the phagocyte compartment (neutrophils, monocytes). These patients
often have problems with mucosal infections ( Gingivitis, osteomyelitis)
h. Very diverse group of disorders affecting complement system. Deficiencies of almost all complement
components have been described. Have a variable spectrum.
Patterns of Infection in Immunodeficiencies [S3]
a. The patterns of infection are going to be concentration of lecture. Don’t try to memorize all laundry lists.
Focus on prototypical disorders for each disease. Example question: Patient scenario – what sorts of
infection the patient has had, what sort of things should you be thinking about?
b. In B cell deficiencies, antibody deficiencies, you are really talking about sinopulmonary infections, and
sometimes GI infections. Practically speaking, patients with Pure B cell deficiencies present with recurrent
sinusitis pneumonia primarily. Some problems with GI problems, particularly with Giardia. Almost always
sinopulmonary infections.
c. For T cell and SCID, talking about opportunistic infections. Occur early in infancy. Patient is born without T
cell function, so they are immediately susceptible to many opportunistic organisms. In the case of B cells,
infections usually start after 3 or 4 months because it takes that long for maternal IgG in blood to disappear.
Fc receptors in placenta transfer immunoglobulins to baby to protect it.
d. The hallmark of phagocyte deficiencies are deep seeded tissue infections (cellulitis, abscesses,
osteomyelitis). Patients can also get terrible pneumonias. Get infections in areas we don’t typically see
infections.
e. Terminal complement components tend to have problems with Neisseria meningitides, the cause of terrible
bacterial meningitis.
f.
T Cell Immunodeficiencies [S4]
a. Pure T cell deficiencies is a relatively small list.
b. DiGeorge/Velocardiofacial is something, especially in dental, is something you may be involved with. This is
strongly associated with congenital heart disease.
c. Also specific deficiencies of the T cell receptor and its associated signaling complex are known. If T cell
receptor doesn’t work well, causes problems with T cells.
d. Zap 70 is an enzyme that transmits signals from activated T cell receptor to interior of cell. This turns out to
be an essential connection to transmit activation signal.
DiGeorge/Velocardiofacial Syndrome [S5]
a. This syndrome is fairly common, dominant disorder. Only need one deletion (usually chromosome 22).
Syndrome presents with pretty severe congenital heart disease, hypoparathyroidism (low blood Ca+ levels).
CLASS: HOUR 2
Scribe: Spencer Terry
DATE 11-17-10
Proof: Ashley Tate
PROFESSOR: Atkinson
Primary Immunodeficiencies
Page 2 of 5
Can lead to seizures and variable degree thymic hypoplasia (can be partial or complete absence of thymus).
If you have no thymus, you will have no mature T cells. Necessary for maturation of T cells.
b.
c.
VI. DiGeorge Syndrome [S6]
a. There is a distinctive facies in this syndrome.
b. Congenital malformation syndrome in which the basis for the disorder is an abnormality of migration of cells
from the 3rd and 4th branchial arches down into the mediastinum.
c. It affects issues related to the branchial arches. Formation of ears are abnormal. Eyes typically have a
downslanting appearances. Frequently micrognathia, a short philtrum, fish shaped mouth. Often have
learning disabilities.
d. Have have a submucous cleft palate, which is important. Occasionally, surgeons have made the mistake of
trying to operate without realizing they had it. Leads to poor outcomes because they have problems with
speech development anyway.
e. Typically lower than normal IQ.
f.
VII. DiGeorge Syndrome: Cardiac Abnormalities [S7]
a. They tend to have some of the more severe congenital heart disease.
b. The 3 on slide make up about three quarters of the patients.
c. Usually present with severe congenital heart disease, but recently some patients have presented in
adolescence with other symptoms, maybe related to hypothyroidism, immune system, or some other heart
defect.
d.
VIII. Picture [S8]
a. Diagnosed using FISH (Fluorescent in-situ hybridization). This technique is very useful for diagnosing big
deletions on chromosomes.
b. A probe is fluorescently labeled that binds to a specific region. There are two probes here. These are
chromosome that are duplicated and ready for mitosis, stained red. Then differently colored probes are
added. One binds to telomeric end of chromosome 22. The other probe is specific for the region that is
deleted in chromosome 22.
c. This is a normal control sample
d.
IX. Picture [S9]
a. This is a patient sample.
b. The labeled chromosome in the center is normal. Has both probes.
c. The other chromosome to left has only the telomeric probe and is missing the probe at the deletion area.
d. Often times, parents can be diagnosed that never had the heart problems.
e. The actual number of T cells that graduate from the thymus are directly proportional to the size of the thymus.
Can chop out lobes of thymus and T cell graduation decreases.
f. Every once in a while, a patient is found that has no T cells at all, and this is not compatible with life. Don’t
live long enough to become a SCID
g. These patients can’t be helped with bone marrow transplant because it is the thymus that has the problem.
The treatment would be a thymus transplant (Only done at Duke)
h. For all other severe disorders, bone marrow transplant is the treatment of choice
X. Severe Combined Immunodeficiency Syndromes (SCID) [S10]
a. This is one of the laundry lists that we don’t have to remember.
b. Picked out the top one to talk about because it is seen the most.
c. All of these impair T cell function at least, if not T and B cell function directly.
d. X linked SCID is by far the most common (about 40% of SCID), because it is on the X chromosome and only
one mutation is required. The rest are autosomal recessive mutations.
e.
f.
XI. Common Features of Severe Combined Immunodeficiency (SCID) [S11]
a. SCID is a syndrome. In pediatrics, called failure to thrive syndrome, where the patient is not growing
normally and meeting developmental milestones. May be having increased infections.
b. The list of things that can cause failure to thrive syndrome is very long, from parental neglect to inherited
problems to toxicity, etc.
c. Primary immune deficiences are certainly part of the syndrome.
CLASS: HOUR 2
Scribe: Spencer Terry
DATE 11-17-10
Proof: Ashley Tate
PROFESSOR: Atkinson
Primary Immunodeficiencies
Page 3 of 5
d. Often have the onset of infections in neonatal because of no T cells. Often are opportunistic.
e. Chronic or recurrent thrush, chronic rashes, chronic or recurrent diarrhea. When you look at the patient, you
don’t see what you normally do in a patient with recurrent thrush. Don’t see lymph nodes in the neck, or
tonsilar tissue.
XII. Severe Combined Immunodeficiency Common Laboratory Features[S12]
a. Laboratory abnormalities that are quite characteristic.
b. Usually have low immunoglobulins. Don’t all get diagnosed in early infancy.
c. This condition is not compatible with life beyond a year or two. Going to die of some type of infection if they
are not diagnosed.
d. They may be undiagnosed for a number of months if they have gone through primary series of
immunizations.
e. Won’t make antibodies at all. If you test T cells for response using mitogen (plant protein that binds to sugar
molecules on surface of cell) to stimulate cells to divide. In a cell culture, they divide like crazy. In these
patients however, nothing happens.
f. Analyze using flow cytometry to identify different cell populations. Have low T cells, B cells, and lymphocytes.
XIII. Severe Combined Immunodeficiency Treatment[S13]
a. Bone marrow transplant is treatment of choice.
b. Gene therapy is becoming more common. Ultimately the treatment of choice, but is still a new technology.
c.
XIV.
Picture [S14]
a. Worst case scenaria. Baby that picked up varicella, possibly from 12 month immunization. This patient has
varicella that is resistant to treatment. Liver and brain are also infected in this infant.
b.
XV. B Cell Immunodeficiencies [S15]
a. These almost always present with chronic sinopulmonary infections.
b. Another long laundry list. Might be worth remember Bruton’s Agammaglobulinemia. This is quite compatible
with life if you replace the immunoglobulin because their T cells work normally and they don’t have problems
with other aspects of the immune system. These patients do well with monthly immunoglobulin
c. There are a variety of other severe immunoglobulin deficiencies, and some are common.
d. Selective IgA deficiency is the most common, present in 1 in 600 people from northern Europe. Uncommon
elsewhere.
e. Common variable immunodeficiency – know 4 genes that cause this disease, but don’t know the main gene
yet. Seems to be closely related to these other diseases. People with IgG subclass deficiency may progress
to the very severre common variable immunodeficiency. This disease is one you can see in a young adult
that has gradually started having sinopulmonary infections and eventually pneumonia. Late onset type
disease.
f. Main problem with these diseases is the inability to trigger B cell maturation. Have normal numbers, but not
differentiating into plasma cells.
XVI.
IgG Subclass – IgA-D –CVID Polar Ends of a Common Disease? [S16]
a. We know there is a link because in family studies of patients with common variable immunodeficiency, up to
half of their children have selective IgA deficiency, and many have been noted to progress to CVID.
XVII. Common Variable Immunodeficiency [S17]
a. These are the features of the disease.
b. The primary immunodeficiency disease, or at least the most common one that could present in an older
person that you wouldn’t expect to see it. Someone with an unremarkable childhood and now as an adult, is
presenting with worsening and recurrent infections.
XVIII. IgG Subclass and IgA Deficiencies Patterns of Illness [S18]
XIX.
Combined Immunodeficiencies [S19]
a. This is a shortlist. Have not exhausted the list of diseases. Not so much interested in you memorizing the
diseases.
b. Wiskott-Alrich syndrome is a syndrome of eczema, thrombocytopenia, immunodeficiency. Is a disease in
which the defective gene has to do with cytoskeletal arrangements. Platelets don’t typically work very well.
The rest of immune system is also dysfunctional.
c. Ataxia-Telangiectasia is a DNA repair disorder. In a disease like this, X-rays are something that is really bad
for the patient, because the patient can’t repair defects very well. Leads to increased chance of developing
malignancies. Also have problems recombining T and B cell receptors.
d. Hyper-IgM syndrome is a syndrome in which the B cells are unable to switch. Not given the proper signals.
Can make IgM, but can’t switch to other isotypes.
CLASS: HOUR 2
Scribe: Spencer Terry
DATE 11-17-10
Proof: Ashley Tate
PROFESSOR: Atkinson
Primary Immunodeficiencies
Page 4 of 5
e. X linked lymphoproliferative disorder – at least 3 genes are known now that can cause this. Have particular
problems with infection mono.
f. Chronic mucocutaneous candidiasis – patients have chronic thrush often with skin infections, nail infections,
etc. Definitely an association with autoimmunity
g. Hyper-IgE syndrome – markedly elevated IgE. At least one gene (STAT3) is known. Causes a diffuse block in
a number of cytokine receptors and defects in phagocyte and T and B cell function. Also associated with
some strange dental abnormalities. Many of these patients with dominant form don’t shed their primary
dentition.
XX. Hyper-IgE Syndrome [S20]
a. Coarse facies, retention of primary dentition, and terrifying infections with all kinds of different things.
b. Have absence of a type of T cell that is important in protecting you from extracellular infections. Called a
TH17 cell.
XXI.
NEMO Deficiency [S21]
a. Another cause of combined immunodeficiency. NEMO is a regulator protein that is involved with the
activation of NF kappa B, which is the center of the universe for T cell activation. Very complicated
transcription factor that has most complicated activation.
b. Deficiency of this molecule is associated with ectodermal dysplasia. As such, often has abnormal hair and
teeth.
XXII. Diagram [S22]
a. NF Kappa B sits in the center. This is a small number of the receptors that feed through to activate the T cell.
XXIII. Picture [S23}
a. Example of some of the dental defects. Don’t have to have these, but often have sparse and conical dentition
often seen in ectodermal dysplasia.
XXIV. Other Cellular Immunodeficiencies: [S24]
a. Another group of disorders that are involved with susceptibility to viruses. Those are defects in natural killer
cells and cytotoxic T cells. These are the two main type of cells that eliminate viral infections from the body,
so if you don’t have these, you aren’t going to be able to get rid of it. These infections are very severe.
XXV. Familial Hemophagocytic Lymphohistiocytosis (FHL) [S25]
XXVI. Defects in the Interferon-gamma / Interleukin-12 Pathway [S26]
XXVII. IL-12/IFN-gamma Pathway Defects [S27]
XXVIII. Numerous Acid Fast Organisms [S28]
XXIX. Phagocyte Deficiencies [S29]
a. Phagocyte deficiencies are things you may see occasionally.
b. Chronic granulomatous disease is the prototypical disease.
c. All of these diseases are hard to transplant, and transplanters hate to do it. To transplant a patient, have to
eradicate the T cells in a patient that is already immunosuppressed.
d. These patients are not often transplanted, but the Leukocyte adhesion defect patients are, because it is too
severe to be compatible with life otherwise.
e. A lot of the chronic granulomatous disease patients continue on into adulthood and are susceptible to many
infections.
XXX. Chronic Granulomatous Disease [S30]
a. Chronic granulomatous disease is a disease that is marked by inability of phagocytes to generate hydrogen
peroxide. 5 genes are known that can cause this condition.
b. Infected by organisms that are catalase positive. Can destroy hydrogen peroxide
c. These patients get terrible granulomatous infections that are hard to clear up.
XXXI. Chronic Granulomatous Disease: Diagnosis [S31]
a. The NBT is not used very much anymore. The one used now is mostly a flow cytometric test, called DHR.
XXXII. Picture [S32]
a. This is the NBT test.
XXXIII. DHR Flow Cytometric Assay [S33]
a. The one used now is the Flow cytometric assay.
b. The flow cytometer analyzes the cells for colors generated by lasers, one at a time in a high speed flow in
front of the lasers. Then tells you how bright the cells are fluorescing.
c. The cells are loaded with this red dye and stimulated to see if they make hydrogen peroxide. The brighter, or
more red they are, the more hydrogen peroxide they produce.
d. The patient had X linked granulomatous disease. The father had normal peak, all cells fluoresced normally.
The mother had 2 peaks. One normal, and then another peak that didn’t change much after activated. This is
because there is a process called lyonization in the blood. In females, their blood cells do not use both X
CLASS: HOUR 2
Scribe: Spencer Terry
DATE 11-17-10
Proof: Ashley Tate
PROFESSOR: Atkinson
Primary Immunodeficiencies
Page 5 of 5
chromosomes – one is inactivated randomly. In this case, the mother’s neutrophils are using about equal
amounts of each chromosome.
e. The patient’s didn’t move at all. Not making any hydrogen peroxide at all.
XXXIV. CGD patient with skin infections [S34]
a. Here is the patient with all these skin infections. In this case Serratia.
b. The patient would get antibiotic treatments and partly cleared up. Then get off antibiotics and the infection
comes right back.
XXXV. Leukocyte Adhesion Deficiency I [S35]
a. A very severe deficiency in which the patient’s neutrophils are unable to bind to the endothelium. Neutrophils
are basically trapped within the vasculature. Unable to go to sites of infection, make pus, etc. These patients
usually go to transplant.
b. Often get mucosal infections.
c. Even though they have tons of white cells, they aren’t able to get to the tissues to do anything.
XXXVI. Omphalitis in LAD I patient [S36]
a. Omphalitis is an infection of the umbilical stump. This patient got an infection at the first wound he ever
received.
XXXVII. Chediak-Higashi Syndrome [S37]
a. There are several other related diseases to which we know several genes.
b. These have to do with abnormal granule formation. Can lead to a number of things:
i. Hypopigmentation/partial albinism because the hair granules are not normally formed either
ii. Neurologic problems because granules from neuron endings are not secreted normally.
iii. Bleeding problems because platelets don’t work correctly
iv. Immunologic problems because granules aren’t secreted to kill viral infected cells and phagocytes don’t
work well (can’t secrete granules into lysosomes)
XXXVIII.
Picture [S38]
a. Blood slide.
b. Blocky granules
c. Can see blocky granules of pigment in a patients hair
XXXIX. Complement and Infection [S39]
a. Very complex system, with over 30 cell bound and circulating proteins. Deficiencies of almost all of these
components are known.
b. They produce a variable degree of immunodeficiency.
c. The classical pathway is activated by antibody. Antibody bound to surfaces, multiple igG molecules, or one
IgM molecule, or immune complexes where they are frequently deposited.
d. Defects with this part of the complement system is associated with autoimmunity.
e. With C1 deficiency, almost the patients that have been found have a lupus like disorder.
f. The characteristic findings in people with terminal deficiencies are recurrent infections with Neisseria,
particularly the one that causes meningitis.
g. Patients with early alternative pathway and with C3 deficiency can have severe infections anywhere. These
would be patients you would be particularly worried about getting bacteremic during a dental procedure.
Might require a little more care with antibiotics and such.
XL. Complement Deficiencies: [S40]
a. There are a couple of tests.These are hemolytic assays. If you want to know if the patient has a defect in the
classical pathway, there is a single test you can do. If blood is handled properly, low CH50 with normal AH50
means the patient has a defect in early classical pathway.
b. A low AH50 and normal CH50 means a defect in the early alternative.
c. If a defect in both of them, it means they are either consuming complement somehow, or they have a defect
in one of the terminal pathways.
d. CH50 measures integrity of proteins in classical pathway. Very useful.
e. To check alternate pathway, which includes C3b, B, P, can do same test and check for AH50
XLI.
Picture [S41]
a. Remember, don’t worry about laundry lists.
b. Focus on types of infections you would see in certain patients, etc.
[End 45:29 mins]